IE61094B1 - Process for preparing DI-n-propylacetonitrile - Google Patents

Abstract

Preparation of di-N-propylacetonitrile by a process consisting in heating N-1-propyl-N-butylformamide to a temperature of between 350 DEG C and 550 DEG C and in the absence of oxygen, in the presence of a catalyst consisting of a silica impregnated with 0.1 to 10% by weight of alkali metal cations.

Description

The present invention relates, generally speaking, to a new process for preparing an acetonitrile derivative. in particular, the invention relates to a new process for preparing di-n-propylacetonitrile of formula: CH„-CH -CH, £ ί CH-CM CH3CH3~CHs Di-n-propylacetonitrile is a known product which is especially useful for the preparation of compounds possessing valuable pharmacological properties.

For example, di-n-propylacetonitrile may be used for the preparation of di-n-propylacetamide or valpromide, or alternatively for the production of di-n-propylacetic acid or valproic acid, as described in Patents Fr-A-2,385,918 and FR-A-2,383,907.

These compounds are currently widely used on account of their neurotropic properties, and especially on account of their antiepileptic properties.

The traditional processes for preparing di-npropylacetonitrile are generally complicated, and require the use of reagents which are dangerous to the manufacturing personnel. For example, the preparation of di-npropyIacetonitri I e from di-n-propyl ketone makes use of sodium cyanide, an extremely toxic product. In addition, some preparation phases consist of a hydrogenation, which is always difficult to carry out on a large scale.

The search for an industrial process for producing di-n-propylacetonitrile starting, for example, with din-propyl ketone, hence remains of fundamental interest.

Processes are already known for preparing aliphatic nitriles from formamide derivatives, by reaction of the latter in the gaseous phase in contact with catalysts, chiefly catalysts based on silica, doped or otherwise. Nevertheless, most of the prior documents relating to these processes specifically describe only the dehydration of formamide derivatives that are incapable either of forming olefins by the breakage of C-N bonds, or of forming isomers. in this connection, there may be mentioned Patent US-A-3,256,311, which shows the preparation of aliphatic nitriles from formsmides at a temperature of between 460°C and 560°C in contact with active silicic acid or with silicates optionally activated with metal oxides of groups III to VI of the Periodic Table of elements, for example titanium oxide. The active silicic acid can, in add i ti on, be combined, if desired, with basic oxides such as calcium oxide, magnesium oxide or aluminium oxide. However, this combination is of no importance. The preparation of acetonitrile from N-methylformamide is specifically described therein, this compound being incapable, however, of forming by-products of the isomeric or ethylenic type.

Similarly, the preparation of aliphatic nitriles also from formamides, by a dehydration/rearrangement reaction at 400-650°C in the presence of a bismuth phos phomolybdate-based catalyst in the presence of small quantities of oxygen, has been reported. A reaction of this kind has been described in Patent FR-A-2,341,562 and its certificate of addition FR-A-2,418,223.

These references essentially teach the dehydration of N-ethylfereaiaide to propionitrile, but make absolutely no mention of the formation of by-products such as ethylene However, it may be noted that experiments performed with N-tert-butylformamide give poor results with respect to selectivity.

In the context of the development of the present invention, attempts were made to prepare di-n-propylacetonitrile by the dehydration of H-(1-propyl-n-butyl) formami de according to the prior methods described above, that is to say employing a catalyst consisting of undoped silica, of silica doped with titanium chloride or alternatively of a bismuth phosphomolybdate.

In all cases, as a consequence of the breakage of C-N bonds, ethylenic by-products were obtained in quantities greater than 10X, capable of reaching, in some cases, more than 20%, as well as more than 2% of isomers of di-n-propylacetonitrile, namely 2-e t h yIhexanenit r iIe and 2-me thyIhep tanen i t r iIe.

For example, the dehydration of N-(1-propyI-n~ butyl)formamide was performed using an undoped silica as catalyst by applying the process below: 13.5 cc of pelletised silica gel (2x3 mm), having the following characteristics: specific surface area : 320 m^/g pore volume :1.75ml/g pH of a 5% strength suspension : 6.0 SiOj content : 99.6% Αΐ2θ3εοηί:δηί :0.15% HagO content : 0.04% are placed in the middle of a 200 cc tubular Pyrex glass reactor (diameter 2 cm, length 32 ca).

The reactor is placed in an electric oven, and the catalyst is pretreated for 20 hours under a nitrogen flux (10 l/h) at 350°C, and 12 g (13.5 raI/h) of N-(1-propyI-n-butyI)formamids and 10 l/h of nitrogen are then introduced via the top of the reactor. The products formed are recovered at the bottom of the reactor by means of two double-walled containers, one maintained at 50°C and the other at -10°C. Gas chromatographic analysis of the crude mixture of products obtained is performed periodically. After 7 hours' operation, it is found that the conversion of H-(1-propyl-n-butyl)foraamide and the selective ty wit h r e s p e c t to the products, expres- sed in ) ί relative to the formam ide converted, does not change. The crude mixture then has the following composi- tion: Heptanes * 22.5% Di-n-propylmethylamine 9 3.0% Di-n-propylacetonitrile β 66.5% 2-Ethylhexanenitrile 1.9% 2-Hethylheptanenitrile 0.5% Unconverted N- (1-prooyl-n-butyl) form- amide 5.6% Conversion of H-(1-propyl-n-butyl)formamide is hence 94.42 for a 66.5X yield of di-n-propylacetnnitrile. In addition, a production of heptenes of more than 202 (double bond at the 1" or 2-position as minor components, at the 3-position predominant) and of isomers of d i - npropylacetonitrile of approximately 2.52 are observed.

Accordingly, the process thus described cannot be used for the future preparation of di-n-propylacetamide or di-n-propylacetic acid, as the di-n-propylacetonitrile obtained is contaminated with too many by-products. In effect, according to the pharmaceutical standards in force, di-n-propylacetamide or di n-propylacetic acid cannot contain more than 0.4; purities.

It has now been found, unexpectedly, that it is possible to prepare di-n-propy I ace tοn i t r iIe according to a continuous process, by employing the high-temperature dehydration of H-(1-propyI-n-butyI)ΐormamide in the presence of a catalyst based on silica doped with a basic element, while considerably reducing the formation of by-products.

Thus, di-n-propylacetoni£riIe is prepared according to the invention by heating M-(1-propyl-n-butyl) formal» ide of formula: CW,-CH -CH ,i£ -CM.

'CM-MM-CM or d i - • or i in- it is to a temperature of between 35O°C and 55O°C, preferably between 40Q°C and 500°C, in the absence of oxygen, in th® presence of a catalyst consisting of a silica impregnated with 0.1 to 102 by weight, and preferably with of alkali metal cations such as, for example, He' or K', thereby yielding the desired compound.

The catalysts used in the process of the invention are prepared from silica gels having a specific surface area preferably of between 200 and 500 m /g, and a pore volume preferably of between 0.8 and 2.0 ml/g. 0.25 to 22 by weigh Silica gels of this type are commercially available, or may be prepared from aqueous solutions of sodium silicate by precipitation with ammonia solution» are then impregnated with alkali say brought into contact, at room temperature, with an aqueous solution of an alkali metal hydroxide or an alkali metal salt such as, for example,» an alkali metal carbonate. The silica gels thus impregnated can then, after drying for 10 to 24 hours at 150— 200°C, be shaped by extrusion or pelletizing according to customary techniques.

Regeneration of the catalyst in question after a sufficiently long operating time,, in order to enable its initial activity to be restored,» is carried out by treatment under diluted oxygen at a temperature that permits combustion of the coke formed. A treatment of this type fully restores the activity and selectivity of this catalyst .

The catalytic dehydration of N-i1-propyl~n-butyl)~ formamid® is preferably performed by a gaseousphase reaction on a fixed bed of catalyst at high temperature, generally 400 to 500°C. The use of such a , the absence These silica gels reaction necessitates, at these temperatures of oxygen, which leads to successive decomposition reactions of the organic molecules present. It is therefore necessary to perform the process of the invention under an inert gas such as nitrogen or argon.

Catalysts based on silica gel, used in the process or tl invention, are of cons irable value on account of the fact that they enable di-n-propylacetonitrile to be prepared in yields of the order of 80 to 85% while avoiding the production of heptenes, and while bring ing the content of isomers of di-n-propyI acetonitrile down to a level below 0.1%.

Accordingly, the invention also relates to a catalyst for carrying out the process according to the invention, consisting of a silica impregnated with 0.Ί to 10% by weight of alkali metal or alkaline earth metal cations, as described above.

M-(l-Propyl-n-butyl)formam ide is a known product, described in Chimie Tfisrapeutique, Mo. 5,pp. 388-391 (1972) as a compound which is difficult to prepare and unstable by nature since it changes with the passage of time. it has been found , in the context of the present invention,, that N - ( 1 -p r opy I-n-bu t y I ) f o r m am i de may be readily prepared by the action in the heated state, for example at a temperature of 130 to 150°C, of an excess of an alkyl formate, such as ethyl formate, on di-n-propylmethylamine. In this way, a oure and fully defined compound is obtained in a yield of more than 95%, this compound being stable at room temperature.

As regards di-n-propy I methyLamine, this is also a known compound according to Chimie Therapeutique, cited above. This amine may be obtained in an especially advantageous aanner by the reaction of di-n-propyImethanol or di-n-propylacetone with ammonia and hydrogen in the presence of a nickel-based catalyst, for example Raney nickel, the reaction faking place at a temperature of between 150 and 180°C.

According to this process, a yield of di-n-propylmethylaraine of more than 952 is obtained.

The following non-limiting examples illustrate the i invent i on: EXAMPLE 1; Preparation of di-n-propylacetonitrile A) 0i-n-propyImethylaraine A mixture consisting of di-n-propyl ketone/ammonia/ hydrogen in the mole ratio 1:5:5 is passed at a pressure 5 of 4.5 x 10 Pa through a tubular reactor (diameter: 2.5 ca; length; 60 cm) containing 50 cc of nickel catalyst (552) supported on kieselguhr. The hourly flow rate of di-n-propyl ketone is 25 cc/h and the temperature setting of the oven is 1750C.

The reaction effluent is recovered at the outlet of the reactor in a condenser maintained at 1Q°C.

Chromatographic analysis of the mixture shows that if consists of 972 of di-n-propy I methyI amine, 12 of tri(di-n-propylamino)heptarie and 12 of di-n-propyl ketone.

B) N-(1-PropyI-n-butyI)formamide A mixture consisting of one mole of di-n-propylmethyI amine and 4 moles of methyl formate is passed through a tubular reactor filled with glass beads (diameter: 2.5 cm length: 60 cm) at a flow rate of 50 cc/h. The heated zone of the reactor corresponds to 100 cc.

A temperature of 150°C is maintained in this portion of the reactor, and the reaction effluent is condensed at the outlet of the reactor in two containers in cascade, one maintained at 35°C and the other at 0°C.

By analysis of the first condenser, a mixture of 982 of N-(1 —propy I-n-butyI)fo rmam i de and 22 of di-n-propyI methyI amine is obtained.

In the second condenser, a mixture of methanol 15 and methyl formate is recovered.

C) 0i-n-propyI acetonitriIe a) Catalyst g of silica gel having the following characteristics: specific surface area pore volume pH of a 52 strength suspension S i02 content AI2O3 content 25 NagO content are impregnated in a conventional manner in a solution comprising 10.8 ml of 1 N sodium hydroxide and 150 ml of demineralized water. The solution is evaporated under vacuum at 70°C, and the silica impregnated with 0.542 30 of Ha thereby obtained is placed in the middle of a 200 cc tubular Pyrex reactor (diameter 2 ca, length 32 cm). Th® reactor is placed in an electric oven and the catalyst is then treated under a nitrogen flux (10 l/h) tor 20 hours at 350°C. b) Nitrile g (13.5 ral/h) of N-(1-propy I-n-bu ty I) formats i de and 10 l/h of nitrogen are then injected through a d i f: 320 mc/g : 1.75 mI/g ; 6.0 : 99.62 0.152 : 0-042 fuser via the top of the reactor, brought to 500°C fter 7 hours and' the temperature is operation, the crude product obtained is recovered at the bottom of the reactor by means of two double-walled containers, one maintained at 5Q°C and the other at -10°C. Ouring this operation, gas chromatographic analysis of the mixture of crude products obtained is performed periodically.

In this way, di-n-propyI acetonitriIe is obtained in crude form, that is to say a composition containing: Heptanes Di-n-propylmethylamine Di-n-propylacetonitrile Isomers of di-n-propylacetonitrile Unconverted N-(1-propyl-n-butylHorman) i d e OX „ 3 % 78.3" <0. U 17.42 After the di-n-propylmethylamine is separated off by acid washing and the di-n-propy I ace tonitriIe is distilled off, the di-n-propylmethylamine can be recovered in order to restore the starting forraaroide and the unconverted H-(1-propyl~n~butyl)formamide, in order to recycle it in the dehydration reaction.

EXAMPLE 2 Preparation of di-n-propylacetonitrile a) H-(1-Propyl-n-butyl)formamide 600 g (5.06 moles) of di-n-propylmethylamine and 520 g (7.01 moles) of ethyl formate are introduced, while flushing with nitrogen, into a 1.5 1 reactor equipped with a heating system, a stirrer, a thermometer and a con denser. The mixture is heated at S0°C for 13 hours, and the crude reaction product is then concentrated in a rotary evaporator so as to remove the excess ethyl formate and the unreacted di-n-propylmethylamine. The residue thereby obtained is taken up with 2000 ml of diisopropyl ether, and the resulting mixture is washed successively with 3 times 200 ml of 102 strength aqueous hydrochloric acid and twice 200 ml of water. The organic phase is dried over sodium sulphate and concentrated in a rotary evaporator .

In this way, 656 g of N-(1-propyI-n-butyI)formamide, assaying at 98.62, are obtained.

This compound may be obtained analytically pure by distillation.

B.p 86°C <0.66 Pa). Percentage analysis %: C H N 5 Calculated 67.09 11.96 9 .78 Found I R spec trum (film): 66.74 12.22 9 .69 Associated NH 3300 cm * 1 (m) 3060 _ ι cm ( m ) HC = O 2860 cm ( m ) 10 C = 0 b) Di-n-propylacetoni 1680 cm 1 t r i I e ( f ) The process described in Exempt e 1 is used , em- ploying a catalyst based on the same silica gel, but impregnated on this occasion with 0.8% of K', supplied in the form of potassium hydroxide, prepared under the same conditions as in Example 1.

After 12 hours' operation, crude di-n-propylacetonitrile is obtained, namely a composition containing: Heptenes \ :. 0% 0 i-n-propyl methyl amine : 3.1% 0i-n-propyI acetonitriIe : 83.1% Isomers of di-n-propylacetonitri le : < 0.1% Unconverted M-(1-propyl-n-butyl)format·? ide : 13.8% EXAMPLE 3 Preparation of di-n-propylacetonitrile The process described in Example 1 is used, e«’ ploying a catalyst based on silica gel resulting from the precipitation of sodium silicate- This gel, having a spearea equal to 260 ra /g and a pore volume equal Is subsequently impr^giffiated with of Ma' * di-n-propylacetonitrile, namely the follow30 cific surface to 1.08 ral/g, Crude i ng compos ition : Heptenes 0i-n-propyI methyI amine i-n-propylacetoni tr i le Isomers of di-n-propyIacetonitri Ie Unconverted H-(1-propyl-n-butyl)form2.1% 4.8% 64.2% <0.1% amide 28.8% '} ' is thereby obtained at 450°C after 92 hours' operation.

The catalyst is then subjected to a regeneration for 4 hours at 450°C under a gaseous mixture composed of 99.52 of nitrogen and 0.52 of oxygen at a flow rate of 13.5 I /h, and 16 hours under a 1.52:98.5X oxygen/nitrogen mixture. After this treatment, the injection of N-(1propyl-n-butylJformamide in nitrogen is resumed and, after 155 hours, crude di-n-propyI acetonitri I e is obtained, that is to say a composition of formula: Heptenes : 02 0i-n-propy I me thy I amine : 4.52 9i-n-propyI acetonitriIe : 71.62 Isomers of di-propy I acetonitri I e : < 0.12 Unconverted N-(i-propyl-n-butylί formamide : 23.92 A regeneration of the catalyst is then performed according to the same procedure as above. After resumption of the injection of the reactants under the same conditions as above (temperature: 450°C), crude di-n-propylacetonitrile, namely the following composition: Heptenes Oi-n-propylmethylaaine Oi-n-propylacetonitrile Isomers of di-n-propylacetonitrile Unconverted N-il-propyl-n-butylHorm· 8.22 85.52 < 0.12 6.2% is obtained after 7 hours’ operation.

CLAIMS 1. Process for preparing di-n-propylacetonitrile of

Claims (13)

1. CH 3 “CH 2 -CH 2 CH-CN c/ 3 -ch 2 -ch, 5 characterised in that N-(1-propyl-n-bufcyl)formamide of formula: ’ ch 3 -ch 2 ~ch 2 CH-NH-CH CK 3 -CH 2 -'CH 2 is heated to a temperature of between 350C and 550C, and in the absence of oxygen. In the presence of a catalyst consisting of a silica impregnated with 0.1 to 10% by weight of alkali metal cations, to obtain the desired compound.

2. Process according to claim 1, characterised in that the temperature is between 400 and 500C.

3. Process according to claim 1, characterised in that the catalyst is obtained by the impregnation of a silica gel having a specific surface area of between 200 and 500 m z /

4. Process according to claim 1 or claim 3, characterised in that the catalyst is obtained by the impregnation of a silica gel with an aqueous solution of an alkali metal hydroxide or an alkali metal salt.

5. Process according to claim 1„ 3 or 4, characterised in that the silica is impregnated with 0.25 to '2% by weight of alkali metal cations.

6. Process according to any one of claims 1, 3, 4 or 5, characterised in that the alkali metal is sodium or potassium.

7. Catalyst for carrying out the process according to· any one of claims 1 to 5,, consisting of silica impregnated with 0.1 to 10¾ by weight of alkali metal cations.

8. Catalyst according to claim 7, characterised in that the silica is impregnated with 0.25 to 2% by weight of alkali metal cations.

9. Catalyst according to claim 7 or claim 8, characterised in that th® catalyst is obtained by the impregnation of a silica gel having a specific surface area of between 200 and 500 m 2 /g and a pore volume of between 0.8 and 2.0 ml/g.

10. Catalyst according to any one of claims 7 to 9,, characterised in that the alkali metal cation is Na* or . K*.

11. A process according 'to claim 1 for preparing a di-n-propylacetonitrile of the formula given therein, substantially as hereinbefore described with particular reference to the accompanying Examples

12. A di-n-propylacetonitrile of the formula given in - claim 1, whenever prepared by a process claimed in a preceding claim.

13. A catalyst according to claim 7, substantially as hereinbefore described with particular reference to the accompanying Examples-